Host: The Japanese Society of Toxicology
Name : The 49th Annual Meeting of the Japanese Society of Toxicology
Date : June 30, 2022 - July 02, 2022
Non-clinical safety studies play a crucial role for the evaluation of safety risks in humans in the drug development. However, current non-clinical studies cannot predict safety risks sufficiently, which cause a gap known as "Death Valley" between non-clinical and clinical.
Cytokine release syndrome (CRS) is a variety of symptoms caused by cytokine release, including fever, tachypnea, headache, tachycardia, hypotension, skin rash, and hypoxia. CRS is often observed after the administration of biotechnology-derived pharmaceuticals such as antibody drugs, and more recently, after chimeric antigen receptor T cell (CAR-T) therapy and as COVID-19 infection-related symptoms. It is an important issue to avoid and prevent the risks of CRS in the drug development because severe CRS can lead a lethal condition as cytokine storm. However, it is not easy to estimate the risk of the occurrence of CRS in humans in a routine non-clinical studies because of species differences in immune system itself and binding affinity against target antigen, pharmacological activity, and sensitivity to downstream signals caused by slight differences in amino acid sequence in the target molecule. As a result, Death Valley between non-clinical and clinical has not been filled yet, but has been even widening with a muddy stream of cytokines.
Here, we present a case study of our antibody drug that showed CRS in a clinical trial along with the result of non-clinical evaluation. We would like to discuss the limitations of current prediction methods and challenges to overcome the gap based on our case study.
